Bicyclic hydroxamates as inhibitors of matrix metalloproteinases and/or TNF-alpha converting enzyme (TACE)

ABSTRACT

The present application describes to novel bicyclic hydroxamates derivatives of formula I:  
                 
 
     or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, B 1 , B 2 , R 1 , and C are defined in the present specification, which are useful as inhibitors of matrix metalloproteinases (MMP), TNF-α converting enzyme (TACE), aggrecanase, or a combination thereof.

FIELD OF THE INVENTION

[0001] This invention relates generally to novel bicyclic hydroxamatesas inhibitors of matrix metalloproteinases (MMP), TNF-α convertingenzyme (TACE), aggrecanase or a combination thereof, pharmaceuticalcompositions containing the same, and methods of using the same.

BACKGROUND OF THE INVENTION

[0002] There is now a body of evidence that metalloproteases (MP) areimportant in the uncontrolled breakdown of connective tissue, includingproteoglycan and collagen, leading to resorption of the extracellularmatrix. This is a feature of many pathological conditions, such asrheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration;tumor metastasis or invasion; periodontal disease and bone disease.Normally these catabolic enzymes are tightly regulated at the level oftheir synthesis as well as at their level of extracellular activitythrough the action of specific inhibitors, such asalpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease),which form inactive complexes with the MP's.

[0003] Osteo- and Rheumatoid Arthritis (OA and RA respectively) aredestructive diseases of articular cartilage characterized by localizederosion of the cartilage surface. Findings have shown that articularcartilage from the femoral heads of patients with OA, for example, had areduced incorporation of radiolabeled sulfate over controls, suggestingthat there must be an enhanced rate of cartilage degradation in OA(Mankin et al. J. Bone Joint Surg. 1970, 52A, 424-434). There are fourclasses of protein degradative enzymes in mammalian cells: serine,cysteine, aspartic and metalloproteases. The available evidence supportsthat it is the metalloproteases that are responsible for the degradationof the extracellular matrix of articular cartilage in OA and RA.Increased activities of collagenases and stromelysin have been found inOA cartilage and the activity correlates with severity of the lesion(Mankin et al. Arthritis Rheum. 1978, 21, 761-766, Woessner et al.Arthritis Rheum. 1983, 26, 63-68 and Woessner et al. Arthritis Rheum.1984, 27, 305-312). In addition, aggrecanase has been identified asproviding the specific cleavage product of proteoglycan found in RA andOA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214-22).

[0004] Therefore, metalloproteases (MP) have been implicated as the keyenzymes in the destruction of mammalian cartilage and bone. It can beexpected that the pathogenesis of such diseases can be modified in abeneficial manner by the administration of MP inhibitors, and manycompounds have been suggested for this purpose (see Wahl et al. Ann.Rep. Med. Chem. 1990, 25, 175-184, AP, San Diego).

[0005] Tumor necrosis factor-α (TNF-α) is a cell-associated cytokinethat is processed from a 26kd precursor form to a 17kd active form.TNF-α has been shown to be a primary mediator in humans and in animals,of inflammation, fever, and acute phase responses, similar to thoseobserved during acute infection and shock. Excess TNF-α has been shownto be lethal. There is now considerable evidence that blocking theeffects of TNF-α with specific antibodies can be beneficial in a varietyof circumstances including autoimmune diseases such as rheumatoidarthritis (Feldman et al, Lancet 1994, 344, 1105) and non-insulindependent diabetes melitus. (Lohmander, L. S. et al. Arthritis Rheum.1993, 36, 1214-22) and Crohn's disease (MacDonald et al. Clin. Exp.Immunol. 1990, 81, 301).

[0006] Compounds which inhibit the production of TNF are therefore oftherapeutic importance for the treatment of inflammatory disorders.Recently, TNF-a converting enzyme (TACE), the enzyme responsible forTNF-α release from cells, were purified and sequenced (Black et alNature 1997, 385, 729; Moss et al Nature 1997, 385, 733). This inventiondescribes molecules that inhibit this enzyme and hence the secretion ofactive TNF-α from cells. These novel molecules provide a means ofmechanism based therapeutic intervention for diseases including but notrestricted to septic shock, haemodynamic shock, sepsis syndrome, postischemic reperfusion injury, malaria, Crohn's disease, inflammatorybowel diseases, mycobacterial infection, meningitis, psoriasis,congestive heart failure, fibrotic diseases, cachexia, graft rejection,cancer, diseases involving angiogenesis, autoimmune diseases, skininflammatory diseases, OA, RA, multiple sclerosis, radiation damage,hyperoxic alveolar injury, periodontal disease, HIV and non-insulindependent diabetes melitus.

[0007] Since excessive TNF-α production has been noted in severaldisease conditions also characterized by MMP-mediated tissuedegradation, compounds which inhibit both MMPs and TNF-α production mayalso have a particular advantage in diseases where both mechanisms areinvolved.

[0008] Prostaglandins (PG) play a major role in the inflammation processand the inhibition of PG production has been a common target ofanti-inflammatory drug discovery. Many NSAIDS have been found to preventthe production of PG by inhibiting the enzyme cyclooxygenase (COX).Among the two isoforms of COXs, COX-1 is constitutively expressed. COX-2is an inducible isozyme associated with inflammation. Selective COX-2inhibitor was believed to maintain the efficacy of traditional NSAIDs,which inhibit both isozymes, and produce fewer and less drastic sideeffects. As a result, development of selective COX-2 inhibitors hasattracted major interest in the pharmaceutical industry. Because of thesignificant roles of PGs and TNF-α in inflammation, combined use ofCOX-2 and TACE inhibitors may have superior efficacy to either therapyalone in some inflammatory diseases.

[0009] U.S. Pat. No. 5,506,242, U.S. Pat. No. 5,552,419, and U.S. Pat.No. 5,672,615 disclose matrix metalloproteases inhibitors of theformula:

[0010] wherein Ar is carbocyclic or heterocyclic aryl; R and R₁ togetherwith the chain to which they are attached form a1,2,3,4-tetrahydroisoquinoline; R₂ can be hydrogen. The compounds ofU.S. Pat. No. 5,506,242, U.S. Pat. No. 5,552,419, and U.S. Pat. No.5,672,615 are not considered to be part of the presently claimedinvention.

[0011] WO97/18194 (U.S. Pat. No. 6,207,672) depicts matrixmetalloproteases inhibitors of the formula:

[0012] wherein A can be HO—NH—C(O)—; R¹ can be R²—X-Ph-B-; X is a bondor a single chain atom spacer; R² is unsubstituted or substitutedphenyl; and, Q forms a ring as defined in WO97/18194. These compoundsare not considered to be part of the present invention.

[0013] WO98/08850 illustrates matrix metalloproteases inhibitors of theformula:

[0014] wherein R₁ is hydrogen; R₂ can be hydrogen; W can be arylene orheteroarylene bridge between two adjacent carbons forming a fused ring.These compounds are not considered to be part of the present invention.

[0015] DE 19542189 presents matrix metalloproteases inhibitors of theformula:

[0016] wherein R¹ can be R⁵—X-Ph-A-; A is C₁₋₄ alkylene or —CH═CH—; X isa bond or a single chain atom spacer. These compounds are not consideredto be part of the present invention.

[0017] U.S. Pat. No. 5,866,587 describes matrix metalloproteasesinhibitors of the formula:

[0018] wherein m and n are identical or different, represent 0, 1, 2; Arepresents an aryl ring or heterocycle; X represents —SO₂—, —CO—,—SO₂NH—; and R₅ represents optionally substituted alkyl,(C₃₋₇)cycloalkyl, aryl or heterocyclic. These compounds are notconsidered to be part of the present invention.

[0019] U.S. Pat. No. 5,962,471 describes matrix metalloproteasesinhibitors of the formula:

[0020] wherein R¹ is unsubstituted or substituted phenyl orhetereocycle; A is a bond, O, —CH═CH—, or —C≡C—; B is C₁₋₃ alkylene,—O—C₁₋₅ alkylene- or —CH═CH—; X is —CH═CH—, oxygen or sulfur; and R² canbe HO(H)N—. These compounds are not considered to be part of the presentinvention.

[0021] U.S. Pat. No. 6,225,311 discloses hydroxamic acid derivatives ofthe formula:

[0022] wherein X can be SO₂; Y is aryl or heteroaryl; Z can be O, NH,CH₂ or S; R₂ can be hydrogen; R₄ and R₅ can be hydrogen; and R₁ and R₃together with the atoms to which they are attached can form a divalentmoiety of the formula:

[0023] wherein A is aryl or heteroaryl. These compounds are defined asbeing useful as TACE and MMP inhibitors. These compounds are notconsidered to be part of the present invention.

[0024] WO00/23443 illustrates TNF-α production inhibitors of theformula:

[0025] wherein R¹ is an optionally substituted C₁₋₆ alkyl, phenyl, orheteroaryl. These compounds are not considered to be part of the presentinvention.

[0026] WO00/44730 depicts hydroxamic acid derivatives of the formula:

[0027] These compounds are defined as being useful as TACE and MMPinhibitors. These compounds are not considered to be part of the presentinvention.

[0028] EP 1065209 describes matrix metalloproteases inhibitors of theformula:

[0029] wherein R₂ can be —NHOH; and Ar₁ can be phenyl. These compoundsare not considered to be part of the present invention.

[0030] The compounds of the present invention act as inhibitors of MPs,in particular TACE, MMPs, and/or aggrecanase. These novel molecules areprovided as anti-inflammatory compounds and cartilage protectingtherapeutics. The inhibition of aggrecanase, TACE, and othermetalloproteases by molecules of the present invention indicates theyare anti-inflammatory and should prevent the degradation of cartilage bythese enzymes, thereby alleviating the pathological conditions of OA andRA.

SUMMARY OF THE INVENTION

[0031] Accordingly, the present invention provides novel bicyclichydroxamates useful as MMP and/or TACE inhibitors or pharmaceuticallyacceptable salts or prodrugs thereof.

[0032] The present invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

[0033] The present invention provides a method for treating inflammatorydisorders, comprising: administering to a host, in need of suchtreatment, a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

[0034] The present invention provides a method of treating a conditionor disease mediated by MMPs, TACE, aggrecanase, or a combination thereofin a mammal, comprising: administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

[0035] The present invention provides a method comprising: administeringa compound of the present invention or a pharmaceutically acceptablesalt or prodrug form thereof in an amount effective to treat a conditionor disease mediated by MMPs, TACE, aggrecanase, or a combinationthereof.

[0036] The present invention provides a method for treating inflammatorydisorders, comprising: administering, to a host in need of suchtreatment, a therapeutically effective amount of one of the compounds ofthe present invention, in combination with one or more additionalanti-inflammatory agents selected from selective COX-2 inhibitors,interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAPkinase inhibitors, TNF-α inhibitors, TNF-α sequestration agents, andmethotrexate.

[0037] The present invention provides novel compounds of the presentinvention for use in therapy.

[0038] The present invention provides the use of novel compounds of thepresent invention for the manufacture of a medicament for the treatmentof a condition or disease mediated by MMPs, TACE, aggrecanase, or acombination thereof.

[0039] These and other objects, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of formula (I):

[0040] or pharmaceutically acceptable salt or prodrug forms thereof,wherein A, B, B¹, B², R¹, and C are defined below, are effective MMPand/or TACE inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0041] [1] Thus, in an embodiment, the present invention provides anovel compound of formula I:

[0042] or a stereoisomer or pharmaceutically acceptable salt formthereof, wherein;

[0043] A is selected from: —C(O)NHOH, —C(O)NHOR⁵, —C(O)NHOR⁶,—N(OH)COR⁵, —N(OH)CHO, and —CH₂SH;

[0044] ring B, including B¹ and B², is a 5-7 membered heterocyclic ringsubstituted with 0-1 R²;

[0045] B¹ and B², independently of one another, consist of 0-3 carbonatoms and 0-1 heteroatoms selected from O, N, and S(O)_(p) and aresubstituted with 0-1 carbonyl groups;

[0046] provided that ring B contains other than a N—S, N—O, or N—N bond;

[0047] ring C is a 5-10 membered aromatic ring consisting of 1-9 carbonatoms and 0-4 heteroatoms selected from O, N, and S(O)_(p);

[0048] ring C is substituted with 0-1 R³ and 0-1 R⁴;

[0049] R¹ is U-X-Y-Z-U^(a)-X^(a)-Y^(a)-Z^(a);

[0050] U is selected from: C(O), C(O)O, C(O)NR^(a1), S(O)_(p), andS(O)_(p)NR^(a1);

[0051] X is absent or is selected from: C₁₋₁₀ alkylene, C₂₋₁₀alkenylene, and C₂₋₁₀ alkynylene;

[0052] Y is absent or is selected from: O, NR^(a1), S(O)_(p), and C(O);

[0053] Z is selected from:

[0054] a C₃₋₁₃ carbocycle substituted with 0-5 R^(b); and

[0055] a 5-14 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-5 R^(b);

[0056] U^(a) is absent or is selected from: O, NR^(a1), C(O), C(O)O,OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1), NR^(a1)C(O)O,NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1), NR^(a1)S(O)_(p), andNR^(a1)SO₂NR^(a1);

[0057] X^(a) is absent or is selected from: C₁₋₄ alkylene, C₂₋₄alkenylene, and C₂₋₄ alkynylene;

[0058] Y^(a) is absent or is selected from: O, NR^(a1), S(O)_(p), andC(O);

[0059] provided that U^(a)-X^(a)-Y^(a) forms a spacer of two or moreatoms, other than —CH═CH— or —C≡C—;

[0060] Z^(a) is selected from:

[0061] a C₃₋₁₃ carbocycle substituted with 0-5 R^(c); and

[0062] a 5-14 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-5 R^(c);

[0063] provided that U, Y, Z, U^(a), Y^(a), and Z^(a) do not combine toform a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p)group;

[0064] R² is selected from: H, C₁₋₆ alkyl substituted with 0-1 R^(b),C₂₋₆ alkenyl substituted with 0-1 R^(b), and C₂₋₆ alkynyl substitutedwith 0-1 R^(b);

[0065] R³ is selected from: H, C₁₋₆ alkyl substituted with 0-1 R^(b),

[0066] C₂₋₆ alkenyl substituted with 0-1 R^(b),

[0067] C₂₋₆ alkynyl substituted with 0-1 R^(b),

[0068] C₃₋₁₀ carbocycle substituted with 0-2 R^(b),

[0069] —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(b), and

[0070] —(CH₂)_(r)-5-10 membered heterocycle consisting of carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p) and substituted with 0-2 R^(b);

[0071] R⁴ is selected from: H, C₁₋₆ alkyl substituted with 0-1 R^(b),C₂₋₆ alkenyl substituted with 0-1 R^(b), C₂₋₆ alkynyl substituted with0-1 R^(b), OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a1), NR^(a)C(O)R^(a), C(S)NR^(a)R^(a1),NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, OCF₃, andCF₂CF₃;

[0072] R^(a), at each occurrence, is independently selected from: H andC₁₋₆ alkyl;

[0073] R^(a1), at each occurrence, is independently selected from: H,

[0074] C₁₋₆ alkyl substituted with 0-1 R^(c1),

[0075] C₂₋₆ alkenyl substituted with 0-1 R^(c1),

[0076] C₂₋₆ alkynyl substituted with 0-1 R^(c1), and

[0077] —(CH₂)_(r)-3-8 membered carbocyclic or heterocyclic ringconsisting of carbon atoms and 0-2 ring heteroatoms selected from N,NR^(a2), O, and S(O)_(p) and substituted with 0-3 R^(c1);

[0078] alternatively, R^(a) and R^(a1) when attached to a nitrogen aretaken together with the nitrogen to which they are attached form a 5 or6 membered heterocycle consisting of carbon atoms and from 0-1additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);

[0079] R^(a2), at each occurrence, is independently selected from:

[0080] C₁₋₄ alkyl, phenyl, and benzyl;

[0081] R^(a3), at each occurrence, is independently selected from: H,

[0082] C₁₋₆ alkyl substituted with 0-1 R^(c1),

[0083] C₂₋₆ alkenyl substituted with 0-1 R^(c1),

[0084] C₂₋₆ alkynyl substituted with 0-1 R^(c1),

[0085] —(CH₂)_(r)-3-8 membered carbocyclic or heterocyclic ringconsisting of carbon atoms and 0-2 ring heteroatoms selected from N,NR^(a2), O, and S(O)_(p) and substituted with 0-3 R^(c1);

[0086] R^(b), at each occurrence, is independently selected from:

[0087] C₁₋₆ alkyl substituted with 0-1 R^(c1), OR^(a), Cl, F, Br, I, ═O,—CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),NR^(a)C(O)R^(a), C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1),OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, OCF₃, CF₂CF₃, CHF₂, CH₂F, andphenyl;

[0088] R^(c), at each occurrence, is independently selected from: H,C₁₋₆ alkyl substituted with 0-2 R^(c1), C₂₋₆ alkenyl substituted with0-2 R^(c1), C₂₋₆ alkynyl substituted with 0-2 R^(c1), OR^(a), Cl, F, Br,I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂,(CR^(a)R^(a1))_(n)NR^(a)R^(a1), (CR^(a)R^(a1))_(n)C(═NCN)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(═NR^(a))NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(═NOR^(a))NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(O)NR^(a)OH, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a1), (CR^(a)R^(a1))_(n)C(S)OR^(a1),(CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(n)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(S)NR^(a)R^(a1), (CR^(a)R^(a1))_(n)OC(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(n)NR^(a)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(n)NR^(a)SO₂R^(a3),(CR^(a)R^(a1))_(n)NR^(a)SO₂NR^(a)R^(a1),

[0089] —(CR^(a)R^(a1))_(n)—C₃₋₁₀ carbocycle substituted with 0-2 R^(c1),and

[0090] —(CR^(a)R^(a1))_(n)-5-14 membered heterocycle consisting ofcarbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p) and substituted with 0-2 R^(c1);

[0091] R^(c1), at each occurrence, is independently selected from: H,C₁₋₄ alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a), and S(O)_(p)R^(a);

[0092] R⁵, at each occurrence, is selected from: C₁₋₁₀ alkyl substitutedwith 0-2 R^(b), and C₁₋₈ alkyl substituted with 0-2 R^(e);

[0093] R^(e), at each occurrence, is selected from: phenyl substitutedwith 0-2 R^(b) and biphenyl substituted with 0-2 R^(b);

[0094] R⁶, at each occurrence, is selected from: phenyl, naphthyl, C₁₋₁₀alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆ alkylcarbonyloxy-C₁₋₃alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-, C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl,phenyloxycarbonyloxy-C₁₋₃ alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxy-C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,[5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(═O)R⁹, and —CH(R⁸)OC(═O)OR⁹;

[0095] R⁷ is selected from: H, C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

[0096] R^(7a) is selected from H, C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

[0097] R⁸ is selected from H and C₁₋₄ linear alkyl;

[0098] R⁹ is selected from H, C₁₋₈ alkyl substituted with 1-2 R^(f),C₃₋₈ cycloalkyl substituted with 1-2 R^(f), and phenyl substituted with0-2 R^(b);

[0099] R^(f), at each occurrence, is selected from: C₁₋₄ alkyl, C₃₋₈cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with 0-2 R^(b);

[0100] n, at each occurrence, is selected from: 0, 1, 2, 3, and 4;

[0101] p, at each occurrence, is selected from: 0, 1, and 2; and

[0102] r, at each occurrence, is selected from: 0, 1, 2, 3, and 4;

[0103] provided that:

[0104] (i) when rings B and C form tetrahydroisoquinoline and A is—C(O)NHOH, then R¹ is other than{4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl,{(2-hydroxybenzoyl)amino)}benzenesulfonyl,{(4-fluorophenyl)methoxy}benzenesulfonyl, or{(4-methoxyphenyl)carbamate}benzenesulfonyl;

[0105] (ii) when rings B and C form tetrahydro-furo[2,3-c]pyridine, A is—C(O)NHOH, and U is SO₂, then Z is other than phenyl;

[0106] (iii) when rings B and C form tetrahydro-1H-[1,4]benzodiazepine,A is —C(O)NHOH, U is SO₂, then Z is other than phenyl;

[0107] (iv) when U is SO₂, then U^(a)-X^(a)-Y^(a) is other than—OCH₂—C≡C—, —NHCH₂—C≡C—, —CH₂CH₂—C≡C— or —SCH₂—C≡C—;

[0108] (v) when U is SO₂ and Z is phenyl, then U^(a) is other thanOC(O).

[0109] [2] In another embodiment, the present invention provides a novelcompound, wherein;

[0110] A is selected from: —C(O)NHOH, —C(O)NHOR⁵, —C(O)NHOR⁶,—N(OH)COR⁵, and —N(OH)CHO;

[0111] ring B including B¹ and B² is a 5-6 membered heterocyclic ringsubstituted with 0-1 R²;

[0112] ring C is a 6 membered aryl or 5-6 membered heteroaryl consistingof 1-6 carbon atoms and 0-4 heteroatoms selected from O, N, andS(O)_(p);

[0113] ring C is substituted with 0-1 R³ and 0-1 R⁴;

[0114] X is absent or is selected from: C₁₋₄ alkylene, C₂₋₄ alkenylene,and C₂₋₄ alkynylene;

[0115] Y is absent;

[0116] Z is selected from:

[0117] a C₃₋₁₁ carbocycle substituted with 0-5 R^(b); and

[0118] a 5-11 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-5 R^(b);

[0119] U^(a) is absent or is selected from: O, NR^(a1), C(O), C(O)O,C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), and S(O)_(p)NR^(a1);

[0120] X^(a) is absent or is selected from: C₁₋₄ alkylene, C₂alkenylene, and C₂ alkynylene;

[0121] Y^(a) is absent or is selected from: O and NR^(a1);

[0122] provided that U^(a)-X^(a)-Y^(a) forms a spacer of two or moreatoms, other than —CH═CH— or —C≡C—;

[0123] Z^(a) is selected from:

[0124] a C₃₋₁₃ carbocycle substituted with 0-5 R^(c); and

[0125] a 5-10 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-5 R^(c);

[0126] provided that U, Z, U^(a), Y^(a), and Z^(a) do not combine toform a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p)group;

[0127] R³ is selected from: H, C₁₋₆ alkyl substituted with 0-1 R^(b),

[0128] C₂₋₆ alkenyl substituted with 0-1 R^(b),

[0129] C₂₋₆ alkynyl substituted with 0-1 R^(b),

[0130] C₃₋₆ carbocycle substituted with 0-2 R^(b),

[0131] —CH₂—C₃₋₆ carbocycle substituted with 0-2 R^(b),

[0132] a 5-6 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-2 R^(b), and

[0133] —CH₂-5-6 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-2 R^(b);

[0134] R^(a), at each occurrence, is independently selected from: H andC₁₋₄ alkyl;

[0135] R^(a1), at each occurrence, is independently selected from: H,C₁₋₄ alkyl, phenyl and benzyl;

[0136] alternatively, R^(a) and R^(a1) when attached to a nitrogen aretaken together with the nitrogen to which they are attached form a 5 or6 membered heterocycle consisting of carbon atoms and from 0-1additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);

[0137] R^(b), at each occurrence, is independently selected from: C₁₋₆alkyl, OR^(a), Cl, F, Br, ═O, —CN, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3),CF₃, and OCF₃;

[0138] R^(c), at each occurrence, is independently selected from:

[0139] C₁₋₆ alkyl substituted with 0-1 R^(c1), C₂₋₆ alkenyl substitutedwith 0-1 R^(c1), C₂₋₆ alkynyl substituted with 0-1 R^(c1), OR^(a), Cl,F, Br, ═O, —CN, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a1), (CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1),C₃₋₆ carbocycle and a 5-6 membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p);

[0140] R⁵, at each occurrence, is selected from: C₁₋₆ alkyl substitutedwith 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);

[0141] R⁷ is selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-;

[0142] R^(7a) is selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-; and

[0143] R⁹ is selected from: H, C₁₋₆ alkyl substituted with 1-2 R^(f),C₃₋₆ cycloalkyl substituted with 1-2 R^(f), and phenyl substituted with0-2 R^(b);

[0144] provided that:

[0145] (i) when rings B and C form tetrahydroisoquinoline and A is—C(O)NHOH, then R¹ is other than{4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl,{(2-hydroxybenzoyl)amino)}benzenesulfonyl,{(4-fluorophenyl)methoxy}benzenesulfonyl, or{(4-methoxyphenyl)carbamate}benzenesulfonyl;

[0146] (ii) when rings B and C form tetrahydro-furo[2,3-c]pyridine, A is—C(O)NHOH, and U is SO₂, then Z is other than phenyl.

[0147] [3] In another embodiment, the present invention provides a novelcompound, wherein;

[0148] A is selected from: —C(O)NHOH, and —N(OH)CHO;

[0149] U-X is SO₂, C(O), or C(O)CH₂;

[0150] Z is phenyl substituted with 0-3 R^(b) or pyridyl substitutedwith 0-3 R^(b);

[0151] U^(a) is absent or is selected from: O, NR^(a1), C(O),C(O)NR^(a1), S(O)_(p), and S(O)_(p)NR^(a1);

[0152] X^(a) is absent or is selected from: C₁₋₄ alkylene, C₂alkenylene, and C₂ alkynylene;

[0153] provided that U^(a)-X^(a)-Y^(a) forms a spacer of two or moreatoms and is other than —CH═CH— or —C≡C—;

[0154] Z^(a) is a C₅₋₆ carbocycle substituted with 0-3 R^(c) or a 5-10membered heteroaryl containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p) and substituted with 0-3 R^(c);

[0155] provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form aN—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group;

[0156] R^(a), at each occurrence, is independently selected from: H andC₁₋₄ alkyl;

[0157] R^(a1), at each occurrence, is independently selected from: H,C₁₋₄ alkyl, phenyl and benzyl;

[0158] R^(b), at each occurrence, is independently selected from: C₁₋₄alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃;

[0159] R^(c), at each occurrence, is independently selected from:

[0160] C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a), (CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3),

[0161] (CR^(a)R^(a1)) SO₂NR^(a)R^(a1), and phenyl; and

[0162] R⁵, at each occurrence, is selected from: C₁₋₄ alkyl substitutedwith 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);

[0163] provided that:

[0164] (i) when rings B and C form tetrahydroisoquinoline and A is—C(O)NHOH, then R¹ is other than{4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl,{(2-hydroxybenzoyl)amino)}benzenesulfonyl or{(4-fluorophenyl)methoxy}benzenesulfonyl;

[0165] (ii) when rings B and C form tetrahydro-furo[2,3-c]pyridine, A is—C(O)NHOH, and U is SO₂, then Z is other than phenyl.

[0166] [4] In another embodiment, the present invention provides a novelcompound, wherein;

[0167] A is —C(O)NHOH;

[0168] Z is phenyl substituted with 0-1 R^(b) or pyridyl substitutedwith 0-1 R^(b);

[0169] U^(a) is absent or is O;

[0170] X^(a) is absent or is CH₂ or CH₂CH₂;

[0171] Y^(a) is absent or is O;

[0172] provided that U^(a)-X^(a)-Y^(a) forms a spacer of two or moreatoms, other than —CH═CH— or —C≡C—;

[0173] Z^(a) is selected from: phenyl substituted with 0-3 R^(c),pyridyl substituted with 0-3 R^(c), and quinolinyl substituted with 0-3R^(c);

[0174] provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form aN—N, N—O, O—N, or O—O group;

[0175] R^(a), at each occurrence, is independently selected from: H,CH₃, and CH₂CH₃;

[0176] R^(a1), at each occurrence, is independently selected from: H,CH₃, and CH₂CH₃;

[0177] R^(a2), at each occurrence, is independently selected from: H,CH₃, and CH₂CH₃;

[0178] R^(c), at each occurrence, is independently selected from:

[0179] C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a), (CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), and (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1);

[0180] r, at each occurrence, is selected from 0, 1, 2, and 3; and,

[0181] n, at each occurrence, is selected from 0, 1, 2, and 3;

[0182] provided that:

[0183] (i) when rings B and C form tetrahydroisoquinoline and A is—C(O)NHOH, then R¹ is other than{4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl or{(4-fluorophenyl)methoxy}benzenesulfonyl;

[0184] (ii) when rings B and C form tetrahydro-furo[2,3-c]pyridine, A is—C(O)NHOH, and U is SO₂, then Z is other than phenyl.

[0185] [5] In another embodiment, the present invention provides a novelcompound selected from the group:

[0186]N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxamide;

[0187]N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxamide;

[0188]N-hydroxy-7-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-6-carboxamide;

[0189]N-hydroxy-7-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-6-carboxamide;

[0190]N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydropyrido[3,4-b]-pyrazine-7-carboxamide;

[0191]N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-7-carboxamide;

[0192]N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine-6-carboxamide;

[0193]N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine-6-carboxamide;

[0194]N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine-6-carboxamide;and

[0195]N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine-6-carboxamide;

[0196] or a pharmaceutically acceptable salt form thereof.

[0197] In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

[0198] In another embodiment, the present invention provides a novelmethod for treating an inflammatory disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltform thereof.

[0199] In another embodiment, the present invention provides a novelmethod of treating a condition or disease mediated by MMPs, TACE,aggrecanase, or a combination thereof in a mammal, comprising:administering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of the present invention or apharmaceutically acceptable salt form thereof.

[0200] In another embodiment, the present invention provides a novelmethod comprising: administering a compound of the present invention ora pharmaceutically acceptable salt form thereof in an amount effectiveto treat a condition or disease mediated by MMPs, TACE, aggrecanase, ora combination thereof.

[0201] In another embodiment, the present invention provides a novelmethod of treating a disease or condition selected from acute infection,acute phase response, age related macular degeneration, alcoholic liverdisease, allergy, allergic asthma, anorexia, aneurism, aortic aneurism,asthma, atherosclerosis, atopic dermatitis, autoimmune disease,autoimmune hepatitis, Bechet's disease, cachexia, calcium pyrophosphatedihydrate deposition disease, cardiovascular effects, chronic fatiguesyndrome, chronic obstruction pulmonary disease, coagulation, congestiveheart failure, corneal ulceration, Crohn's disease, enteropathicarthropathy, Felty's syndrome, fever, fibromyalgia syndrome, fibroticdisease, gingivitis, glucocorticoid withdrawal syndrome, gout, graftversus host disease, hemorrhage, HIV infection, hyperoxic alveolarinjury, infectious arthritis, inflammation, intermittent hydrarthrosis,Lyme disease, meningitis, multiple sclerosis, myasthenia gravis,mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvicinflammatory disease, periodontitis, polymyositis/dermatomyositis,post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis,psoriatic arthritis, pulmonary emphysema, pydoderma gangrenosum,relapsing polychondritis, Reiter's syndrome, rheumatic fever, rheumatoidarthritis, sarcoidosis, scleroderma, sepsis syndrome, Still's disease,shock, Sjogren's syndrome, skin inflammatory diseases, solid tumorgrowth and tumor invasion by secondary metastases, spondylitis, stroke,systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis,and Wegener's granulomatosis.

[0202] In another embodiment, the present invention provides novelcompounds of the present invention for use in therapy.

[0203] In another embodiment, the present invention provides the use ofnovel compounds of the present invention for the manufacture of amedicament for the treatment of a condition or disease mediated by MMPs,TACE, aggrecanase, or a combination thereof.

[0204] In another embodiment, the present invention provides a novelarticle of manufacture, comprising:

[0205] (a) a first container;

[0206] (b) a pharmaceutical composition located within the firstcontainer, wherein the composition, comprises: a first therapeuticagent, comprising: a compound of the present invention or apharmaceutically acceptable salt form thereof; and,

[0207] (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of an inflammatory disorder.

[0208] In another embodiment, the present invention provides a novelarticle of manufacture, comprising:

[0209] (a) a first container;

[0210] (b) a pharmaceutical composition located within the firstcontainer, wherein the composition, comprises: a first therapeuticagent, comprising: a compound of the present invention or apharmaceutically acceptable salt form thereof; and,

[0211] (c) a package insert stating that the pharmaceutical compositioncan be used in combination with a second therapeutic agent to treat aninflammatory disorder.

[0212] In another preferred embodiment, the present invention provides anovel article of manufacture, further comprising:

[0213] (d) a second container;

[0214] wherein components (a) and (b) are located within the secondcontainer and component (c) is located within or outside of the secondcontainer.

[0215] In another embodiment, the present invention provides a methodfor treating inflammatory disorders, comprising: administering, to ahost in need of such treatment, a therapeutically effective amount ofone of the compounds of the present invention, in combination with oneor more additional anti-inflammatory agents selected from selectiveCOX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthaseinhibitors, p38 MAP kinase inhibitors, TNF-α inhibitors, TNF-αsequestration agents, and methotrexate.

[0216] This invention also encompasses all combinations of preferredaspects of the invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment to describe additional even more preferredembodiments of the present invention. It is also understood that eachand every element of any embodiment is intended to be a separatespecific embodiment. Furthermore, any elements of an embodiment aremeant to be combined with any and all other elements from any of theembodiments to describe additional embodiments.

Definitions

[0217] The compounds herein described may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. Geometric isomers of double bonds such as olefinsand C═N double bonds can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. C is and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated. All processes used to prepare compounds of thepresent invention and intermediates made therein are considered to bepart of the present invention.

[0218] Preferably, the molecular weight of compounds of the presentinvention is less than about 500, 550, 600, 650, 700, 750, 800, 850, or900 grams per mole. More preferably, the molecular weight is less thanabout 850 grams per mole. Even more preferably, the molecular weight isless than about 750 grams per mole. Still more preferably, the molecularweight is less than about 700 grams per mole.

[0219] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. When aring system (e.g., carbocyclic or heterocyclic) is said to besubstituted with a carbonyl group or a double bond, it is intended thatthe carbonyl group or double bond be part (i.e., within) of the ring.

[0220] The term “acylation” as used herein describes thefunctionalization of a primary or secondary amine by reacting it with an“acylator” to form a stable compound. Examples of acylators include (butare not limited to) an acid chloride, a carboxylic acid anhydride, asulfonyl chloride, a chloroformate, an isocyanate, an isothiocyanate,etc. the product of which is an amide, a sulfonamide, a carbamate, aurea, and a thiourea respectively.

[0221] The present invention is intended to include all isotopes ofatoms occurring in the present compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. By way ofgeneral example and without limitation, isotopes of hydrogen includetritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0222] The term “independently selected from”, “independently, at eachoccurrence” or similar language, means that the labeled R substitutiongroup may appear more than once and that each appearance may be adifferent atom or molecule found in the definition of that labeled Rsubstitution group. Thus if the labeled R^(a) substitution group appearfour times in a given permutation of Formula I, then each of thoselabeled R^(a) substitution groups may be a different group falling inthe definition of R^(a). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

[0223] When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

[0224] When a bond to a substituent is shown to cross a bond connectingtwo atoms in a ring, then such substituent may be bonded to any atom onthe ring. When a substituent is listed without indicating the atom viawhich such substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

[0225] In cases wherein there are amines on the compounds of thisinvention, these can be converted to amine N-oxides by treatment withMCPBA and or hydrogen peroxides to afford other compounds of thisinvention. Thus, all shown amines are considered to cover both the shownamine and its N-oxide (N→O) derivative.

[0226] As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. C₁₋₁₀ alkyl (or alkylene),is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylgroups. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example -C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl (oralkenylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkenyl groups. “Alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl and propynyl. C₂₋₁₀ alkynyl (oralkynylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkynyl groups.

[0227] “Halo” or “halogen” as used herein refers to fluoro, chloro,bromo, and iodo; and “counterion” is used to represent a small,negatively charged species such as chloride, bromide, hydroxide,acetate, and sulfate.

[0228] As used herein, “carbocycle” or “carbocyclic residue” is intendedto mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of whichmay be saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

[0229] As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized.The nitrogen atom may be substituted or unsubstituted (i.e., N or NRwherein R is H or another substituent, if defined). The heterocyclicring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. As used herein, theterm “aromatic heterocyclic group” or “heteroaryl” is intended to mean astable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or10-membered bicyclic heterocyclic aromatic ring which consists of carbonatoms and 1, 2, 3, or 4 heteroatoms independently selected from thegroup consisting of N, O and S. It is to be noted that total number of Sand O atoms in the aromatic heterocycle is not more than 1.

[0230] Examples of heterocycles include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, carbazolyl, 4H-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl,1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl,1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl,3,4-dihydro-2H-chromen-4-yl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, and pyrazolo[1,5-a]pyridinyl. Also included arefused ring and spiro compounds containing, for example, the aboveheterocycles.

[0231] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

[0232] As used herein, “pharmaceutically acceptable salts” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; andalkali or organic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,and nitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

[0233] The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound that contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0234] Since prodrugs are known to enhance numerous desirable qualitiesof pharmaceuticals (e.g., solubility, bioavailability, manufacturing,etc.) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

[0235] “Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

[0236] As used herein, “treating” or “treatment” cover the treatment ofa disease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

[0237] “Therapeutically effective amount” is intended to include anamount of a compound of the present invention or an amount of thecombination of compounds claimed effective to inhibit a desiredmetalloprotease in a host. The combination of compounds is preferably asynergistic combination. Synergy, as described for example by Chou andTalalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (inthis case, inhibition of the desired target) of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased anti-inflammatory effect, or some otherbeneficial effect of the combination compared with the individualcomponents.

Synthesis

[0238] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below. All references cited hereinare hereby incorporated in their entirety herein by reference.

[0239] The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used.

[0240] A variety of compounds of formula (I) wherein A is hydroxamicacid group are prepared from the corresponding esters or carboxylicacids using several routes known in the literature (Scheme 1). Themethyl ester of 1 (R¹¹=Me) is directly converted to hydroxamic acid 2 bytreatment with hydroxylamine under basic conditions such as KOH or NaOMein solvents such as methanol. The methyl ester of 1 (R¹¹=Me) can also beconverted to O-benzyl protected hydroxamic acid withO-benzylhydroxylamine under similar conditions or using Weinreb'strimethylaluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M.Syn. Commun. 1982, 12, 989) or Roskamp'sbis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J.Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods wellknown in the literature such as hydrogenation using palladium on bariumsulfate in hydrogen, to give compound 2. Alternatively, 2 can beprepared through the carboxylic intermediate 3. Carboxylic acid 3 isconverted to 2 via coupling with hydroxylamine, or its protectedequivalents (O-benzylhydroxylamine or O-t-butyldimethylsiloxyamine)followed by deprotection.

[0241] Compound 1 can be prepared by coupling the corresponding aminewith the carboxylic acid derivative as shown in Scheme 2 to form amides.Coupling with PyBOP and base gives the corresponding amide withunhindered carboxylic acids but more sterically hindered acids requiremore reactive groups such as the corresponding acid chlorides, acidfluorides, or anhydrides.

[0242] A variety of compounds of formula I whereinX-Y-Z-U^(a)-X^(a)-Y^(a)-Z^(a) is a functionalized phenyl group can beprepared by methods described in Scheme 3. Intermediate 5, availablefrom schemes described previously, is converted to phenol 6 byhydrogenolysis. Phenol 6 is used as a common intermediate for structurediversification. Reaction of 6 with an electrophile R^(c)—X provides thealkylated product 7, which alternatively can be synthesized by reacting6 with R^(c)—OH under Mitsunobu conditions to produce 7. Compound 6 mayalso be reacted with acylators such as isocyanates to form carbamates,as depicted in product structure 8. Treatment of compound 6 with triflicanhydride yields an intermediate aryl triflate which can participate inthe Suzuki reaction with vinyl boronic acids in the presence of Pd(0)catalysts to form intermediate 9. The olefin in intermediate 9 can bereduced directly to compound 10 or alternatively, oxidized with MCPBA toan intermediate epoxide and rearranged with BF₃OEt₂ to form ketone 11.Esters 7, 8, 10, and 11 are converted to the hydroxamic acids followingthe sequences outlined in Scheme 1.

[0243] An alternative to the amidation of amine 4 as describedpreviously in Scheme 2 is the acylation of 4 with a variety of otherfunctional groups, some of which are depicted in Scheme 4. Esters 12-14are then converted to their corresponding hydroxamates using the methodsdescribed in Scheme 1.

[0244] Although the hydroxamic acid of structure 2 is an importantcomponent of MMP inhibition, the heterocycle can be synthesized withnon-hydroxamate substitution such as a mercaptomethyl functional group.As shown in Scheme 5, the final compound 18 may be derived from an ester4 via hydrolysis of the ester and selective borane reduction of thecarboxylic acid to give compound 16. The primary hydroxyl can betransposed to the primary thiol in a number of ways, shown here isMitsunobu addition of thioacetic acid followed by hydrolysis to givecompound 18.

[0245] A series of compounds containing a quinazoline core stucture wereassembled using synthetic Scheme 6. 2,3-dimethylquinazoline 19 istreated with N-chlorosuccinimide and dibenzoylperoxide to chlorinate thebenzylic positions. Treatment of 20 with diethyl(N-acetylamino)malonateunder basic conditions followed by sodium hydride annulates the ring toform 21. Deacetylation and hydrolytic decarboxylation are accomplishedusing HCl(aq) and the carboxylate is re-esterified using acidic MeOH togive 23. Hydroxamate 24 is formed by functionalizing the amine ofcompound 23 with acylators using the methods outlined in Schemes 2-4followed by conversion of the ester to the hydroxamic acid 24 asdiscussed above.

[0246] Other substituted quinoline core structures can be made viasubstituted heteroaryl and heterocyclic α-amino acids such as 26 inScheme 7. Many methods exist for making α-amino acids (see for instance:Easton, C. J.; Chem. Rev., 1997, 97,53-82 and references therein) andshown here is the method of O'Donnell (see J. Org. Chem. 1982, 47,2663-2666). Alkylation of glycine benzophenone imine with a benzylicelectrophile yields compound 26 after deprotection of the imine.Treatment of the amino ester with formaldehyde results inPictet-Spengler cyclization to yield the heterocycle 27 that can beacylated using the methods found in Schemes 2-4 and converted tohydroxamate 28 using the methods in Scheme 1.

[0247] In Scheme 8 substituted imidazoles were prepared using theprocedure of Neuberger et al (Biochem. J. 1944, 38, 309, 312). Protectedhistidine derivateives such as 29 are functionalized with a variety ofR3 groups and deprotected to give compound 31. Treatment of the aminewith formaldehyde results in Pictet-Spengler type cyclization to yield32 which is esterified under acidic conditions to give 33. Acylation ofthe amine (Schemes 2,3,4) followed by conversion to the hydroxamate(Scheme 1) give the final hydroxamic acid 34.

[0248] The synthesis of core structure 33 is illustrated in Scheme 9using the method of Klutchko et al (J. Med. Chem. 1986, 29, 1953). Thebis-alkyl bromide 29 can be synthesized using methods known to oneskilled in the art of organic synthesis. Esterification of the acidchloride with MeOH gives the methyl ester 30 which can participate in adouble SN2 reaction to yield the protected heterocycle 31.Hydrogenolytic removal of the benzyl group provides the basic corestructure 32 which is functionalized by acylation and subsequenthydroxamate formation using the synthetic methods in Schemes 2-4 andScheme 1 respectively.

[0249] When required, separation of the racemic material can be achievedby HPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605. A chiral compound of FormulaI may also be directly synthesized using a chiral catalyst or a chiralligand, e.g., Andrew S. Thompson, et al, Tetr. Lett. 1995, 36,8937-8940. Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

EXAMPLES

[0250] Abbreviations used in the Examples are defined as follows: “1×”for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius,“eq” for equivalent or equivalents, “g” for gram or grams, “mg” formilligram or milligrams, “mL” for milliliter or milliliters, “¹H” forproton, “h” for hour or hours, “M” for molar, “min” for minute orminutes, “MHz” for megahertz, “MS” for mass spectroscopy, “NMR” fornuclear magnetic resonance spectroscopy, “HPLC” for high performanceliquid chromatography, “rt” for room temperature, “tlc” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”,/“D”, “L”,“R” and “S” are stereochemical designations familiar to those skilled inthe art.

Example 1N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-7-carboxamide

[0251] (1a) 2, 3-bis (chloromethyl)pyrazine

[0252] To a solution of 2,3-dimethylpyrazine (6.27 g, 57.4 mmol) in 100mL of carbon tetrachloride was added N-chlorosuccinimide (16.7 g)followed by benzoyl peroxide (278 mg, 2 mol %) and the solution washeated to reflux for 16 h. The reaction was cooled, more benzoylperoxide (278 mg, 2 mol %) was added and the reaction was refluxed for 5h. The reaction was monitored by TLC until the disappearance of startingpyrazine. The reaction flask was cooled in an ice bath, the solutionfiltered, and the eluent was concentrated and chromatographed on SiO₂using 15% EtOAc in hexane. Obtained 1.14 g of the product (11% yield).MS found: (M+H)⁺=178.

[0253] (1b) Diethyl2-(acetylamino)-2-{[3-(chloromethyl)-2-pyrazinyl]methyl}malonate

[0254] To a solution of 2,3-bis(chloromethyl)pyrazine (2.06 g, 11.64mmol) in 60 mL DCM was added diethyl(N-acetylamino)malonate (2.66 g,11.7 mmol)anhydrous potassium carbonate (4.83, 34.9 mmol) and 18-C-6(154 mg, 5 mol %) and the reaction was stirred for 48 h. The reactionwas filtered through a sintered glass funnel, concentrated, and flashchromatographed on SiO₂ using a 50% to 75% EtOAc in hexane gradient.Obtained 3.06 g or 56% yield of the product. MS found: (M+H)⁺=359.

[0255] (1c) Diethyl 6-acetyl-5,8-dihydropyrido[3,4-b]pyrazine-7,7(6H)-dicarboxylate

[0256] To a solution of 1b (1.1 g, 2.36 mmol) in 40 mL THF was added NaH(170 mg, 4.25 mmol, 60% oil dispersion) under N₂ and the solution wasstirred for 30 min. The reaction was carefully quenched with water andextracted from sat NaHCO₃ 3×with EtOAc. The organic layers were driedwith MgSO₄₁ filtered, concentrated, and chromatographed on SiO₂ using75% EtOAc in hexane to give 640 mg of 1c as an HCl salt (85% yield). MSfound: (M+H)⁺=322.

[0257] (1d) Methyl6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-7-carboxylate

[0258] Compound 1c (0.557 mmol) was dissolved in 6 M HCl (3 mL) andrefluxed for 1.5 h. The reaction was cooled, concentrated in vacuo,taken up in sat HCl in MeOH (10 mL), and refluxed overnight. Thereaction was concentrated in vacuo to give the crude amino ester HClsalt. The crude material was taken up in 10 mL MeOH and HCl (g) wasbubbled through the solution for 30 min. After stirring o/n the reactionwas concentrated and dried under vacuum. To this crude amino ester wasdissolved in 2 mL DMF followed by the addition of{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetic acid (205 mg, 0.67mmol), diisopropyl-ethylamine (486 mL, 2.79 mmol), and lastly PyBOP (377mg, 0.72 mmol). After stirring o/n, the reaction was partitioned betweenEtOAc and sat NaHCO₃ and separated. The organic phase was dried overMgSO₄, filtered, concentrated under vacuum, and passed thorough a SiO₂plug using 10% MeOH in DCM. The residue was purified by HPLC to give 68mg of 1d as a bis-TFA salt (17% yield for 3 steps). MS found:(M+H)⁺=483.

Example 1N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-7-carboxamide

[0259] To 1d bis-TFA salt (62 mg, 0.096 mmol) was added an anhydroussolution of hydroxylamine in MeOH (1.5 mL, 1.64 M). After 30 min, thereaction was concentrated and purified by HPLC to give 25 mg of theproduct 1e (37% yield) as a bis-TFA salt after lyophilization. MS found:(M+H)⁺=484.

[0260] Table 1 contains representative examples of the presentinvention. Each entry in the table is intended to be paired with eachstructural formula at the start of the table. For example, example 1 inTable 1 is intended to be paired with each of the following formulaeA-U. TABLE 1

A B

C D

E

F

G H

I J

K L

M N

O P

Q

R S

T U Ex R₁ 1 {4-[(2,6-dimethylphenyl)methoxy]phenyl}acetyl 2{4-[(3,5-dimethylphenyl)methoxy]phenyl}acetyl 3{4-[(3,5-dimethylphenyl)ethyl]phenyl}acetyl 4{4-[1-(3,5-dimethoxyphenyl)ethoxy]phenyl}acetyl 5{4-[(3,5-dichlorophenyl)methoxy]phenyl}acetyl 6{4-[(2,6-dichlorophenyl)methoxy]phenyl}acetyl 7{4-[(3,5-dibromophenyl)methoxy]phenyl}acetyl 8{4-(phenoxymethyl)phenyl}acetyl 9 (4-benzyloxyphenyl)acetyl 10{4-[(3-aminocarbonyl-5-methylphenyl)methoxy]phenyl}acetyl 11{4-[((1,1′-biphenyl)-2-yl)methoxy]phenyl}acetyl 12{4-[((1,1′-biphenyl)-3-yl)methoxy]phenyl}acetyl 13{4-[(5-methyl-3-(methylsulfonyl)phenyl)methoxy]phenyl}acetyl 14{4-[(2-methyl-1-naphthalenyl)methoxy]phenyl}acetyl 15{4-[(4-methyl-2-naphthalenyl)methoxy]phenyl}acetyl 16{4-[(4-quinolinyl)methoxy]phenyl}acetyl 17{4-[1-(4-quinolinyl)ethoxy]phenyl}acetyl 18{4-[(2-pyridinyl)methoxy)phenyl}acetyl 19{4-[(4-pyridinyl)methoxy]phenyl}acetyl 20{4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl}acetyl 21{4-[2-(4-quinolinyl)ethyl]phenyl}acetyl 22{4-[[1-(2,6-dimethyl-4-pyridinyl)ethoxy]phenyl}acetyl 23{4-[(3,5-dimethyl-4-pyridinyl)methoxy]phenyl}acetyl 24{4-[(2,6-diethyl-4-pyridinyl)methoxy]phenyl}acetyl 25{4-[(2,6-dichloro-4-pyridinyl)methoxy]phenyl}acetyl 26{4-[(2,6-dimethoxy-4-pyridinyl)methoxy]phenyl}acetyl 27{4-[(2-chloro-6-methyl-4-pyridinyl)methoxy]phenyl}acetyl 28{4-[(2-chloro-6-methoxy-4-pyridinyl)methoxy]phenyl}acetyl 29{4-[(2-methoxy-6-methyl-4-pyridinyl)methoxy]phenyl}acetyl 30{4-[2-(1,2,3-benzotriazol-1-yl)ethyl]phenyl}acetyl 31{4-[(2-benzimidazolyl)methoxy]phenyl}acetyl 32{4-[(1,4-dimethyl-5-imidazolyl)methoxy]phenyl}acetyl 33{4-[(3,5-dimethyl-4-isoxazolyl)methoxy]phenyl}acetyl 34{4-[(4,5-dimethyl-2-oxazolyl)methoxy]phenyl}acetyl 35{4-[(2,5-dimethyl-4-thiazolyl)methoxy]phenyl}acetyl 36{4-[(3,5-dimethyl-1-pyrazolyl)ethyl]phenyl}acetyl 37{4-[(1,3-benzodioxo-4-yl)methoxy]phenyl}acetyl 38{4-[(1,3,5-trimethyl-4-pyrazolyl)methoxy]phenyl}acetyl 39{4-[(2,6-dimethyl-4-pyrimidinyl)methoxy]phenyl}acetyl 40{4-[(4,5-dimethyl-2-furanyl)methoxy]phenyl}acetyl 41{4-[(4,5-dimethyl-2-thiazolyl)methoxy]phenyl}acetyl 42{4-[2-(2-oxazolyl)ethyl]phenyl}acetyl 43{4-[2-methyl-4-quinolinyl)ethoxy]phenyl}acetyl 44{4-[(2-methyl-4-quinolinyl)ethyl]phenyl}acetyl 45{4-[(2-methyl-1-oxa-4-quinolinyl)methoxy]phenyl}acetyl 46{4-[(2-methyl-3-pyridinyl)methoxy]phenyl}acetyl 47{4-[(2,5-dimethylbenzyl)oxy]phenyl}acetyl 48{4-{[(2-methyl-4-quinolinyl)methyl]amino}phenyl}acetyl 49{6-[(2-methyl-4-quinolinyl)methoxy]-1-naphthyl}acetyl 506-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4-tetrahydro-1-isoquinolinecarbonyl 516-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4-tetrahydro-1-isoquinolinecarbonyl 52 {4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl53 {4-[2-(1H-benzimidazol-1-yl)ethyl]phenyl}acetyl 54{4-[2-(2-methyl-1H-benzimidazol-1-yl)ethyl]phenyl}acetyl 55{4-[2-(2-isopropyl-1H-benzimidazol-1-yl)ethyl]phenyl}acetyl 56{4-(1H-benzimidazol-2-ylmethoxy]phenyl}acetyl 57{4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]phenyl}acetyl 58{4-[(1-isopropyl-1H-benzimidazol-2-yl)methoxy]phenyl}acetyl 59{4-[(1H-indol-3-yl)ethyl]phenyl}acetyl 60{4-[(5-phenyl-1H-imidazol-1-yl)ethyl]phenyl}acetyl 61{4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]phenyl}acetyl 62{4-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]phenyl}acetyl 63 4-[(2,6-dimethylphenyl)methoxy]benzenesulfonyl64 4-[(3,5-dimethylphenyl)methoxy]benzenesulfonyl 654-[(3,5-dimethylphenyl)ethyl]benzenesulfonyl 664-[1-(3,5-dimethoxyphenyl)ethoxy]benzenesulfonyl 674-[(3,5-dichlorophenyl)methoxy]benzenesulfonyl 684-[(2,6-dichlorophenyl)methoxy]benzenesulfonyl 694-[(3,5-dibromophenyl)methoxy]benzenesulfonyl 704-(phenoxymethyl)benzenesulfonyl 71 4-benzyloxybenzenesulfonyl 724-[(3-aminocarbonyl-5-methylphenyl)methoxy]benzenesulfonyl 734-{[(1,1′-biphenyl)-2-yl]methoxy}benzenesulfonyl 744-[{[(1,1′-biphenyl)-3-yl]methoxy}benzenesulfonyl 754-{[5-methyl-3-(methylsulfonyl)phenyl] methoxy}benzenesulfonyl 764-[(2-methyl-1-naphthalenyl)methoxy]benzenesulfonyl 774-[(4-methyl-2-naphthalenyl)methoxy]benzenesulfonyl 784-[(4-quinolinyl)methoxy]benzenesulfonyl 794-[1-(4-quinolinyl)ethoxy]benzenesulfonyl 804-[(2-pyridinyl)methoxy]benzenesulfonyl 814-[(4-pyridinyl)methoxy]benzenesulfonyl 824-[(2,6-dimethyl-4-pyridinyl)methoxy]benzenesulfonyl 834-[2-(4-quinolinyl)ethyl]benzenesulfonyl 844-[[1-(2,6-dimethyl-4-pyridinyl)ethoxy]benzenesulfonyl 854-[(3,5-dimethyl-4-pyridinyl)methoxy]benzenesulfonyl 864-[(2,6-diethyl-4-pyridinyl)methoxy]benzenesulfonyl 874-[(2,6-dichloro-4-pyridinyl)methoxy]benzenesulfonyl 884-[(2,6-dimethoxy-4-pyridinyl)methoxy]benzenesulfonyl 894-[(2-chloro-6-methyl-4-pyridinyl)methoxy]benzenesulfonyl 904-[(2-chloro-6-methoxy-4-pyridinyl)methoxy]benzenesulfonyl 914-[(2-methoxy-6-methyl-4-pyridinyl)methoxy]benzenesulfonyl 924-[2-(1,2,3-benzotriazol-1-yl)ethyl]benzenesulfonyl 934-[(2-benzimidazolyl)methoxy]benzenesulfonyl 944-[(1,4-dimethyl-5-imidazolyl)methoxy]benzenesulfonyl 954-[(3,5-dimethyl-4-isoxazolyl)methoxy]benzenesulfonyl 964-[(4,5-dimethyl-2-oxazolyl)methoxy]benzenesulfonyl 974-[(2,5-dimethyl-4-thiazolyl)methoxy]benzenesulfonyl 984-[(3,5-dimethyl-1-pyrazolyl)ethyl]benzenesulfonyl 994-[(1,3-benzodioxo-4-yl)methoxy]benzenesulfonyl 1004-[(1,3,5-trimethyl-4-pyrazolyl)methoxy]benzenesulfonyl 1014-[(2,6-dimethyl-4-pyrimidinyl)methoxy]benzenesulfonyl 1024-[(4,5-dimethyl-2-furanyl)methoxy]benzenesulfonyl 1034-[(4,5-dimethyl-2-thiazolyl)methoxy]benzenesulfonyl 1044-[2-(2-oxazolyl)ethyl]benzenesulfonyl 1054-[2-methyl-4-quinolinyl)ethoxy]benzenesulfonyl 1064-[(2-methyl-4-quinolinyl)ethyl]benzenesulfonyl 1074-[(2-methyl-1-oxo-4-quinolinyl)methoxy]benzenesulfonyl 1084-[(2-methyl-3-pyridinyl)methoxy]benzenesulfonyl 1094-[(2,5-dimethylbenzyl)oxy]benzenesulfonyl 1094-{[(2-methyl-4-quinolinyl)methyl]amino}benzenesulfonyl 1106-[(2-methyl-4-quinolinyl)methoxy]-1-naphthenesulfonyl 1116-[(2-methyl-4-quinolinyl)methoxy]-1,2,3,4-tetrahydro-1-isoquinolinosulfonyl 1126-[(2-methyl-4-quinolinyl)methyl]-1,2,3,4-tetrahydro-1-isoquinolinosulfonyl 1134-[2-(1H-benzimidazol-1-yl)ethyl]benzenesulfonyl 1144-[2-(2-methyl-1H-benzimidazol-1-yl)ethyl]benzenesulfonyl 1154-[2-(2-isopropyl-1H-benzimidazol-1-yl)ethyl]benzenesulfonyl 1164-(1H-benzimidazol-2-ylmethoxy]benzenesulfonyl 1174-[(1-methyl-1H-benzimidazol-2-yl)methoxy]benzenesulfonyl 1184-[(1-isopropyl-1H-benzimidazol-2-yl)methoxy]benzenesulfonyl 1194-[(1H-indol-3-yl)ethyl]benzenesulfonyl 1204-[(5-phenyl-1H-imidazol-1-yl)ethyl]benzenesulfonyl 1214-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]benzenesulfonyl 1224-[2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]benzenesulfonyl 1234-[(2-methyl-4-quinolinyl)methoxy]benzenesulfonyl

Utility

[0261] The compounds of formula I are expected to possess matrixmetalloprotease and/or aggrecanase and/or TNF-α inhibitory activity. TheMMP inhibitory activity of the compounds of the present invention isdemonstrated using assays of MMP activity, for example, using the assaydescribed below for assaying inhibitors of MMP activity. The compoundsof the present invention are expected to be bioavailable in vivo asdemonstrated, for example, using the ex vivo assay described below. Thecompounds of formula I are expected to have the ability tosuppress/inhibit cartilage degradation in vivo, for example, asdemonstrated using the animal model of acute cartilage degradationdescribed below.

[0262] The compounds provided by this invention should also be useful asstandards and reagents in determining the ability of a potentialpharmaceutical to inhibit MPs. These would be provided in commercialkits comprising a compound of this invention.

[0263] Metalloproteinases have also been implicated in the degradationof basement membranes to allow infiltration of cancer cells into thecirculation and subsequent penetration into other tissues leading totumor metastasis (Stetler-Stevenson, Cancer and Metastasis Reviews, 9,289-303, 1990). The compounds of the present invention should be usefulfor the prevention and treatment of invasive tumors by inhibition ofthis aspect of metastasis.

[0264] The compounds of the present invention should also have utilityfor the prevention and treatment of osteopenia associated with matrixmetalloprotease-mediated breakdown of cartilage and bone that occurs inosteoporosis patients.

[0265] Compounds that inhibit the production or action of TACE and/orAggrecanase and/or MMP's are potentially useful for the treatment orprophylaxis of various inflammatory, infectious, immunological ormalignant diseases or conditions. Thus, the present invention relates toa method of treating various inflammatory, infectious, immunological ormalignant diseases. These include acute infection, acute phase response,age related macular degeneration, alcoholic liver disease, allergy,allergic asthma, anorexia, aneurism, aortic aneurism, asthma,atherosclerosis, atopic dermatitis, autoimmune disease, autoimmunehepatitis, Bechet's disease, cachexia (including cachexia resulting fromcancer or HIV), calcium pyrophosphate dihydrate deposition disease,cardiovascular effects, chronic fatigue syndrome, chronic obstructionpulmonary disease, coagulation, congestive heart failure, cornealulceration, Crohn's disease, enteropathic arthropathy (includinginflammatory bowl disease), Felty's syndrome, fever, fibromyalgiasyndrome, fibrotic disease, gingivitis, glucocorticoid withdrawalsyndrome, gout, graft versus host disease, hemorrhage, HIV infection,hyperoxic alveolar injury, infectious arthritis, inflammation,intermittent hydrarthrosis, Lyme disease, meningitis, multiplesclerosis, myasthenia gravis, mycobacterial infection, neovascularglaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis,polymyositis/dermatomyositis, post-ischaemic reperfusion injury,post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonaryemphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter'ssyndrome, rheumatic fever, rheumatoid arthritis (including juvenilerheumatoid arthritis and adult rheumatoid arthritis), sarcoidosis,scleroderma, sepsis syndrome, Still's disease, shock, Sjogren'ssyndrome, skin inflammatory diseases, solid tumor growth and tumorinvasion by secondary metastases, spondylitis, stroke, systemic lupuserythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'sgranulomatosis.

[0266] Some compounds of the present invention have been shown toinhibit TNF production in lipopolysacharride stimulated mice, forexample, using the assay for TNF induction in mice and in human wholeblood as described below.

[0267] Some compounds of the present invention have been shown toinhibit aggrecanase, a key enzyme in cartilage breakdown, as determinedby the aggrecanase assay described below.

[0268] The compounds of the present invention can be administered aloneor in combination with one or more additional anti-inflammatory agents.These agents include, but are not limited to, selective COX-2inhibitors, interleukin-1 antagonists, dihydroorotate synthaseinhibitors, p38 MAP kinase inhibitors, TNF-α inhibitors, and TNF-αsequestration agents.

[0269] By “administered in combination” or “combination therapy” it ismeant that a compound of the present invention and one or moreadditional therapeutic agents are administered concurrently to themammal being treated. When administered in combination each componentmay be administered at the same time or sequentially in any order atdifferent points in time. Thus, each component may be administeredseparately but sufficiently closely in time so as to provide the desiredtherapeutic effect.

[0270] The term selective COX-2 inhibitors, as used herein, denotesagents that selectively inhibit COX-2 function. Such agents include, butare not limited to, celecoxib (Celebrex®) rofecoxib (Vioxx®), meloxicam(Movicox®), etoricoxib, and valdecoxib.

[0271] TNF-α sequestration agents that may be used in combination withthe compounds of this invention, are TNF-α binding proteins oranti-TNF-α antibodies. These agents include, but are not limited to,etanercept (Enbrel®), infliximab (Remicade®), adalimumab (D2E7), CDP-571(Humicade®), and CDP-870.

[0272] Other anti-inflammatory agents that may be used in combinationwith the compounds of this invention, include, but are not limited to,methotrexate, interleukin-1 antagonists (e.g., anakinra (Kineret®)),dihydroorotate synthase inhibitors (e.g., leflunomide (Arava®)), and p38MAP kinase inhibitors.

[0273] Administration of the compounds of the present invention (i.e., afirst therapeutic agent) in combination with at least one additionaltherapeutic agent (i.e., a second therapeutic agent), preferably affordsan efficacy advantage over the compounds and agents alone, preferablywhile permitting the use of lower doses of each (i.e., a synergisticcombination). A lower dosage minimizes the potential of side effects,thereby providing an increased margin of safety. It is preferred that atleast one of the therapeutic agents is administered in a sub-therapeuticdose. It is even more preferred that all of the therapeutic agents beadministered in sub-therapeutic doses. Sub-therapeutic is intended tomean an amount of a therapeutic agent that by itself does not give thedesired therapeutic effect for the condition or disease being treated.Synergistic combination is intended to mean that the observed effect ofthe combination is greater than the sum of the individual agentsadministered alone.

[0274] As used herein “μg” denotes microgram, “mg” denotes milligram,“g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigmastands for the Sigma-Aldrich Corp. of St. Louis, Mo.

[0275] A compound is considered to be active if it has an IC₅₀ or K_(i)value of less than about 10 μM for the inhibition of a desired MP.Preferred compounds of the present invention have K_(i)'s or IC₅₀'s of≦1 μM. More preferred compounds of the present invention have K_(i)'s orIC₅₀'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s or IC₅₀'s of ≦0.01 μM. Still more preferredcompounds of the present invention have K_(i)'s or IC₅₀'s of ≦0.001 μM.

[0276] Aggrecanase Enzymatic Assay

[0277] A novel enzymatic assay was developed to detect potentialinhibitors of aggrecanase. The assay uses active aggrecanase accumulatedin media from stimulated bovine nasal cartilage (BNC) or relatedcartilage sources and purified cartilage aggrecan monomer or a fragmentthereof as a substrate.

[0278] The substrate concentration, amount of aggrecanases time ofincubation and amount of product loaded for Western analysis wereoptimized for use of this assay in screening putative aggrecanaseinhibitors. Aggrecanase is generated by stimulation of cartilage sliceswith interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α) or otherstimuli. Matrix metalloproteinases (MMPs) are secreted from cartilage inan inactive, zymogen form following stimulation, although active enzymesare present within the matrix. We have shown that following depletion ofthe extracellular aggrecan matrix, active MMPs are released into theculture media (Tortorella, M. D. et al. Trans. Ortho. Res. Soc. 1995,20, 341). Therefore, in order to accumulate BNC aggrecanase in culturemedia, cartilage is first depleted of endogenous aggrecan by stimulationwith 500 mg/ml human recombinant IL-β for 6 days with media changesevery 2 days. Cartilage is then stimulated for an additional 8 dayswithout media change to allow accumulation of soluble, activeaggrecanase in the culture media. In order to decrease the amount ofother matrix metalloproteinases released into the media duringaggrecanase accumulation, agents which inhibit MMP-1, -2, -3, and -9biosynthesis are included during stimulation. This BNC conditionedmedia, containing aggrecanase activity is then used as the source ofaggrecanase for the assay. Aggrecanase enzymatic activity is detected bymonitoring production of aggrecan fragments produced exclusively bycleavage at the Glu373-Ala374 bond within the aggrecan core protein byWestern analysis using the monoclonal antibody, BC-3 (Hughes, C E, etal., Biochem J 306:799-804, 1995). This antibody recognizes aggrecanfragments with the N-terminus, 374ARGSVIL, generated upon cleavage byaggrecanase. The BC-3 antibody recognizes this neoepitope only when itis at the N-terminus and not when it is present internally withinaggrecan fragments or within the aggrecan protein core. Other proteasesproduced by cartilage in response to IL-1 do not cleave aggrecan at theGlu373-Ala374 aggrecanase site; therefore, only products produced uponcleavage by aggrecanase are detected. Kinetic studies using this assayyield a Km of 1.5+/−0.35 μM for aggrecanase.

[0279] To evaluate inhibition of aggrecanase, compounds are prepared as10 mM stocks in DMSO, water or other solvents and diluted to appropriateconcentrations in water. Drug (50 μL) is added to 50 μL ofaggrecanase-containing media and 50 μL of 2 mg/ml aggrecan substrate andbrought to a final volume of 200 μL in 0.2 M Tris, pH 7.6, containing0.4 M NaCl and 40 mM CaCl₂. The assay is run for 4 hr at 37° C.,quenched with 20 mM EDTA and analyzed for aggrecanase-generatedproducts. A sample containing enzyme and substrate without drug isincluded as a positive control and enzyme incubated in the absence ofsubstrate serves as a measure of background.

[0280] Removal of the glycosaminoglycan side chains from aggrecan isnecessary for the BC-3 antibody to recognize the ARGSVIL epitope on thecore protein. Therefore, for analysis of aggrecan fragments generated bycleavage at the Glu373-Ala374 site, proteoglycans and proteoglycanfragments are enzymatically deglycosylated with chondroitinase ABC (0.1units/10 μg GAG) for 2 hr at 37° C. and then with keratanase (0.1units/10 μg GAG) and keratanase II (0.002 units/10 μg GAG) for 2 hr at37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH6.5. After digestion, aggrecan in the samples is precipitated with 5volumes of acetone and resuspended in 30 μL of Tris glycine SDS samplebuffer (Novex®) containing 2.5% beta mercaptoethanol. Samples are loadedand then separated by SDS-PAGE under reducing conditions with 4-12%gradient gels, transferred to nitrocellulose and immunolocated with1:500 dilution of antibody BC3. Subsequently, membranes are incubatedwith a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatasesecond antibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10-30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

[0281] TNF PBMC Assay

[0282] Human peripheral blood mononuclear cells (PBMC) were obtainedfrom normal donor blood by leukophoresis and isolated by Ficoll-Paquedensity separation. PBMCs were suspended in 0.5 ml RPMI 1640 with noserum at 2×10⁶ cells/ml in 96 well polystyrene plates. Cells werepreincubated 10 minutes with compound, then stimulated with 1 μg/ml LPS(Lipopolysaccharide, Salmonella typhimurium) to induce TNF production.After an incubation of 5 hours at 37° C. in 95% air, 5% CO₂ environment,culture supernatants were removed and tested by standard sandwich ELISAfor TNF production.

[0283] TNF Human Whole Blood Assay

[0284] Blood is drawn from normal donors into tubes containing 143 USPunits of heparin/10 ml. 225 ul of blood is plated directly into sterilepolypropylene tubes. Compounds are diluted in DMSO/serum free media andadded to the blood samples so the final concentration of compounds are50, 10, 5, 1, 0.5, 0.1, and 0.01 μM. The final concentration of DMSOdoes not exceed 0.5%. Compounds are preincubated for 15 minutes beforethe addition of 100 mg/ml LPS. Plates are incubated for 5 hours in anatmosphere of 5% CO₂ in air. At the end of 5 hours, 750 ul of serum freemedia is added to each tube and the samples are spun at 1200 RPM for 10minutes. The supernatant is collected off the top and assayed forTNF-alpha production by a standard sandwich ELISA. The ability ofcompounds to inhibit TNF-alpha production by 50% compared to DMSOtreated cultures is given by the IC₅₀ value.

[0285] TNF Induction in Mice

[0286] Test compounds are administered to mice either I.P. or P.O. attime zero. Immediately following compound administration, mice receivean I.P. injection of 20 mg of D-galactosamine plus 10 μg oflipopolysaccharide. One hour later, animals are anesthetized and bled bycardiac puncture. Blood plasma is evaluated for TNF levels by an ELISAspecific for mouse TNF. Administration of representative compounds ofthe present invention to mice results in a dose-dependent suppression ofplasma TNF levels at one hour in the above assay.

[0287] MMP Assays

[0288] The enzymatic activities of recombinant MMP-1, 2, 3, 7, 8, 9, 10,12, 13, 14, 15, and 16 were measured at 25° C. with a fluorometric assay(Copeland, R. A. et al. Bioorganic Med. Chem. Lett. 1995, 5, 1947-1952).Final enzyme concentrations in the assay were between 0.05 and 10 nMdepending on the enzyme and the potency of the inhibitor tested. Thepermissive peptide substrate, MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂, waspresent at a final concentration of 10 μM in all assays. Initialvelocities, in the presence or absence of inhibitor, were measured asslopes of the linear portion of the product progress curves. IC50 valueswere determined by plotting the inhibitor concentration dependence ofthe fractional velocity for each enzyme, and fitting the data bynon-linear least squares methods to the standard isotherm equation(Copeland, R. A. Enzymes: A practical Introduction to Structure,Mechanism and Data Analysis, Wiley-VHC, New York, 1996, pp 187-223). Allof the compounds studied here were assumed to act as competitiveinhibitors of the enzyme, binding to the active site Zn atom aspreviously demonstrated by crystallographic studies of MMP-3 complexedwith related hydroxamic acids (Rockwell, A. et al. J. Am. Chem. Soc.1996, 118, 10337-10338). Based on the assumption of competitiveinhibition, the IC50 values were converted to Ki values as previouslydescribed.

[0289] Compounds tested in the above assay are considered to be activeif they exhibit a K_(i) of ≦10 μM. Preferred compounds of the presentinvention have K_(i)'s of ≦1 μM. More preferred compounds of the presentinvention have K_(i)'s of ≦0.1 μM. Even more preferred compounds of thepresent invention have K_(i)'s of ≦0.01 μM. Still more preferredcompounds of the present invention have K_(i)'s of ≦0.001 μM.

[0290] Using the methodology described above, a number of compounds ofthe present invention were found to exhibit K_(i)'s of ≦10 μM, therebyconfirming the utility of the compounds of the present invention.

[0291] The present invention also encompasses an article of manufacture.As used herein, article of manufacture is intended to include, but notbe limited to, kits and packages. The article of manufacture of thepresent invention, comprises: (a) a first container; (b) apharmaceutical composition located within the first container, whereinthe composition, comprises: a first therapeutic agent, comprising: acompound of the present invention or a pharmaceutically acceptable saltform thereof; and, (c) a package insert stating that the pharmaceuticalcomposition can be used for the treatment of an inflammatory disorder(as defined previously). In another embodiment, the package insertstates that the pharmaceutical composition can be used in combination(as defined previously) with a second therapeutic agent to treat aninflammatory disorder. The article of manufacture can further comprise:(d) a second container, wherein components (a) and (b) are locatedwithin the second container and component (c) is located within oroutside of the second container. Located within the first and secondcontainers means that the respective container holds the item within itsboundaries.

[0292] The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

[0293] The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

[0294] The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Dosage and Formulation

[0295] The compounds of the present invention can be administered orallyusing any pharmaceutically acceptable dosage form known in the art forsuch administration. The active(ingredient can be supplied in soliddosage forms such as dry powders, granules, tablets or capsules, or inliquid dosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

[0296] The compounds of the present invention can be administered insuch oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups, and emulsions.Likewise, they may also be administered in intravenous (bolus orinfusion), intraperitoneal, subcutaneous, or intramuscular form, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts. An effective but non-toxic amount of the compounddesired can be employed as an antiinflammatory and antiarthritic agent.

[0297] The compounds of this invention can be administered by any meansthat produces contact of the active agent with the agent's site ofaction in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butgenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

[0298] The dosage regimen for the compounds of the present inventionwill, of course, vary depending upon known factors, such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter, or arrest the progress of thecondition.

[0299] By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70kg of body weight, this translates into a dosage of 70 to 1400 mg/day.Intravenously, the most preferred doses will range from about 1 to about10 mg/kg/minute during a constant rate infusion. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

[0300] The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

[0301] In the methods of the present invention, the compounds hereindescribed in detail can form the active ingredient, and are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients, or carriers (collectively referred to herein as carriermaterials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

[0302] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

[0303] The compounds of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

[0304] Compounds of the present invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

[0305] Dosage forms (pharmaceutical compositions) suitable foradministration may contain from about 1 milligram to about 100milligrams of active ingredient per dosage unit. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-95% by weight based on the total weight of thecomposition.

[0306] The active ingredient can be administered orally in solid dosageforms, such as capsules, tablets, and powders, or in liquid dosageforms, such as elixirs, syrups, and suspensions. It can also beadministered parenterally, in sterile liquid dosage forms.

[0307] Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

[0308] Liquid dosage forms' for oral administration can contain coloringand flavoring to increase patient acceptance. In general, water, asuitable oil, saline, aqueous dextrose (glucose), and related sugarsolutions and glycols such as propylene glycol or polyethylene glycolsare suitable carriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0309] Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

Capsules

[0310] Capsules are prepared by conventional procedures so that thedosage unit is 500 milligrams of active ingredient, 100 milligrams ofcellulose and 10 milligrams of magnesium stearate.

[0311] A large number of unit capsules may also prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate. Syrup Wt. % ActiveIngredient 10 Liquid Sugar 50 Sorbitol 20 Glycerine  5 Flavor, Colorantand Preservative as required Water as required

[0312] The final volume is brought up to 100% by the addition ofdistilled water. Aqueous Suspension Wt. % Active Ingredient 10 SodiumSaccharin 0.01 Keltrol ® (Food Grade Xanthan Gum) 0.2 Liquid Sugar 5Flavor, Colorant and Preservative as required Water as required

[0313] Xanthan gum is slowly added into distilled water before addingthe active ingredient and the rest of the formulation ingredients. Thefinal suspension is passed through a homogenizer to assure the eleganceof the final products. Resuspendable Powder Wt. % Active Ingredient 50.0Lactose 35.0 Sugar 10.0 Acacia 4.7 Sodium Carboxylmethylcellulose 0.3

[0314] Each ingredient is finely pulverized and then uniformly mixedtogether. Alternatively, the powder can be prepared as a suspension andthen spray dried. Semi-Solid Gel Wt. % Active Ingredient 10 SodiumSaccharin 0.02 Gelatin 2 Flavor, Colorant and Preservative as requiredWater as required

[0315] Gelatin is prepared in hot water. The finely pulverized activeingredient is suspended in the gelatin solution and then the rest of theingredients are mixed in. The suspension is filled into a suitablepackaging container and cooled down to form the gel. Semi-Solid PasteWt. % Active Ingredient 10 Gelcarin ® (Carrageenin gum) 1 SodiumSaccharin 0.01 Gelatin 2 Flavor, Colorant and Preservative as requiredWater as required

[0316] Gelcarin® is dissolved in hot water (around 80° C.) and then thefine-powder active ingredient is suspended in this solution. Sodiumsaccharin and the rest of the formulation ingredients are added to thesuspension while it is still warm. The suspension is homogenized andthen filled into suitable containers. Emulsifiable Paste Wt. % ActiveIngredient 30 Tween ® 80 and Span ® 80 6 Keltrol ® 0.5 Mineral Oil 63.5

[0317] All the ingredients are carefully mixed together to make ahomogenous paste.

Soft Gelatin Capsules

[0318] A mixture of active ingredient in a digestible oil such assoybean oil, cottonseed oil or olive oil is prepared and injected bymeans of a positive displacement pump into gelatin to form soft gelatincapsules containing 100 milligrams of the active ingredient. Thecapsules are washed and dried.

Tablets

[0319] Tablets may be prepared by conventional procedures so that thedosage unit is 500 milligrams of active ingredient, 150 milligrams oflactose, 50 milligrams of cellulose and 10 milligrams of magnesiumstearate.

[0320] A large number of tablets may also be prepared by conventionalprocedures so that the dosage unit was 100 milligrams of activeingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 milligrams of microcrystalline cellulose, 11milligrams of starch and 98.8 milligrams of lactose. Appropriatecoatings may be applied to increase palatability or delay absorption.

Injectable

[0321] A parenteral composition suitable for administration by injectionis prepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspension

[0322] An aqueous suspension is prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

[0323] The compounds of the present invention may be administered incombination with a second therapeutic agent, especially non-steroidalanti-inflammatory drugs (NSAID's). The compound of Formula I and suchsecond therapeutic agent can be administered separately or as a physicalcombination in a single dosage unit, in any dosage form and by variousroutes of administration, as described above.

[0324] The compound of Formula I may be formulated together with thesecond therapeutic agent in a single dosage unit (that is, combinedtogether in one capsule, tablet, powder, or liquid, etc.). When thecompound of Formula I and the second therapeutic agent are notformulated together in a single dosage unit, the compound of Formula Iand the second therapeutic agent may be administered essentially at thesame time, or in any order; for example the compound of Formula I may beadministered first, followed by administration of the second agent. Whennot administered at the same time, preferably the administration of thecompound of Formula I and the second therapeutic agent occurs less thanabout one hour apart, more preferably less than about 5 to 30 minutesapart.

[0325] Preferably the route of administration of the compound of FormulaI is oral. Although it is preferable that the compound of Formula I andthe second therapeutic agent are both administered by the same route(that is, for example, both orally), if desired, they may each beadministered by different routes and in different dosage forms (that is,for example, one component of the combination product may beadministered orally, and another component may be administeredintravenously).

[0326] The dosage of the compound of Formula I when administered aloneor in combination with a second therapeutic agent may vary dependingupon various factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above.

[0327] Particularly when provided as a single dosage unit, the potentialexists for a chemical interaction between the combined activeingredients. For this reason, when the compound of Formula I and asecond therapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with asustained-release material which effects a sustained-release throughoutthe gastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

[0328] These as well as other ways of minimizing contact between thecomponents of combination products of the present invention, whetheradministered in a single dosage form or administered in separate formsbut at the same time by the same manner, will be readily apparent tothose skilled in the art, once armed with the present disclosure.

[0329] The present invention also includes pharmaceutical kits useful,for example, in the treatment or prevention of osteoarthritis orrheumatoid arthritis, which comprise one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I. Such kits may further include, if desired,one or more of various conventional pharmaceutical kit components, suchas, for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

[0330] In the present disclosure it should be understood that thespecified materials and conditions are important in practicing theinvention but that unspecified materials and conditions are not excludedso long as they do not prevent the benefits of the invention from beingrealized.

[0331] Although this invention has been described with respect tospecific embodiments, the details of these embodiments are not to beconstrued as limitations. Various equivalents, changes and modificationsmay be made without departing from the spirit and scope of thisinvention, and it is understood that such equivalent embodiments arepart of this invention.

What is claimed is:
 1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein; A is selected from: —C(O)NHOH, —C(O)NHOR⁵, —C(O)NHOR⁶,—N(OH)COR⁵, —N(OH)CHO, and —CH₂SH; ring B, including B¹ and B², is a 5-7membered heterocyclic ring substituted with 0-1 R²; B¹ and B²,independently of one another, consist of 0-3 carbon atoms and 0-1heteroatoms selected from O, N, and S(O)_(p) and are substituted with0-1 carbonyl groups; provided that ring B contains other than a N—S,N—O, or N—N bond; ring C is a 5-10 membered aromatic ring consisting of1-9 carbon atoms and 0-4 heteroatoms selected from O, N, and S(O)_(p);ring C is substituted with 0-1 R³ and 0-1 R⁴; R¹ isU-X-Y-Z-U^(a)-X^(a)-Y^(a)-Z^(a); U is selected from: C(O), C(O)O,C(O)NR^(a1), S(O)_(p), and S(O)_(p)NR^(a1); X is absent or is selectedfrom: C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene; Y isabsent or is selected from: O, NR^(a1), S(O)_(p), and C(O); Z isselected from: a C₃₋₁₃ carbocycle substituted with 0-5 R^(b); and a 5-14membered heterocycle consisting of carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-5 R^(b); U^(a) is absent or is selected from: O, NR^(a1), C(O),C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1); X^(a) is absent or is selectedfrom: C₁₋₄ alkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene; Y^(a) isabsent or is selected from: O, NR^(a1), S(O)_(p), and C(O); providedthat U^(a)-X^(a)-Y^(a) forms a spacer of two or more atoms, other than—CH═CH— or —C≡C—; Z^(a) is selected from: a C₃₋₁₃ carbocycle substitutedwith 0-5 R^(c); and a 5-14 membered heterocycle consisting of carbonatoms and 1-4 heteroatoms selected from the group consisting of N, O,and S(O)_(p) and substituted with 0-5 R^(c); provided that U, Y, Z,U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O,S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R² is selected from:H, C₁₋₆ alkyl substituted with 0-1 R^(b), C₂₋₆ alkenyl substituted with0-1 R^(b), and C₂₋₆ alkynyl substituted with 0-1 R^(b); R³ is selectedfrom: H, C₁₋₆ alkyl substituted with 0-1 R^(b), C₂₋₆ alkenyl substitutedwith 0-1 R^(b), C₂₋₆ alkynyl substituted with 0-1 R^(b), C₃₋₁₀carbocycle substituted with 0-2 R^(b), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-2 R^(b), and —(CH₂)_(r)-5-10 membered heterocycleconsisting of carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(b); R⁴ isselected from: H, C₁₋₆ alkyl substituted with 0-1 R^(b), C₂₋₆ alkenylsubstituted with 0-1 R^(b), C₂₋₆ alkynyl substituted with 0-1 R^(b),OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), NR^(a)C(O)R^(a), C(S)NR^(a)R^(a1),NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a),S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1),OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, OCF₃, andCF₂CF₃; R^(a), at each occurrence, is independently selected from: H andC₁₋₆ alkyl; R^(a1), at each occurrence, is independently selected from:H, C₁₋₆ alkyl substituted with 0-1 R^(c1), C₂₋₆ alkenyl substituted with0-1 R^(c1), C₂₋₆ alkynyl substituted with 0-1 R^(c1), and —(CH₂)_(r)-3-8membered carbocyclic or heterocyclic ring consisting of carbon atoms and0-2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p) andsubstituted with 0-3 R^(c1); alternatively, R^(a) and R^(a1) whenattached to a nitrogen are taken together with the nitrogen to whichthey are attached form a 5 or 6 membered heterocycle consisting ofcarbon atoms and from 0-1 additional heteroatoms selected from N,NR^(a2), O, and S(O)_(p); R^(a2), at each occurrence, is independentlyselected from: C₁₋₄ alkyl, phenyl, and benzyl; R^(a3), at eachoccurrence, is independently selected from: H, C₁₋₆ alkyl substitutedwith 0-1 R^(c1), C₂₋₆ alkenyl substituted with 0-1 R^(c1), C₂₋₆ alkynylsubstituted with 0-1 R^(c1), —(CH₂)_(r)-3-8 membered carbocyclic orheterocyclic ring consisting of carbon atoms and 0-2 ring heteroatomsselected from N, NR^(a2), O, and S(O)_(p) and substituted with 0-3R^(c1); R^(b), at each occurrence, is independently selected from: C₁₋₆alkyl substituted with 0-1 R^(c1), OR^(a), Cl, F, Br, I, ═O, —CN, NO₂,NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), NR^(a)C(O)R^(a),C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),S(O)_(p)R^(a3), CF₃, OCF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl; R^(c), ateach occurrence, is independently selected from: H, C₁₋₆ alkylsubstituted with 0-2 R^(c1), C₂₋₆ alkenyl substituted with 0-2 R^(c1),C₂₋₆ alkynyl substituted with 0-2 R^(c1), OR^(a), Cl, F, Br, I, ═O, —CN,NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂, (CR^(a)R^(a1))_(n)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(═NCN)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(═NR^(a))NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(═NOR^(a))NR^(a)R^(a1),(CR^(a)R^(a1))_(n)C(O)NR^(a)OH, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a1), (CR^(a)R^(a1))_(n)C(S)OR^(a1),(CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(n)NR^(a)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(S)NR^(a)R^(a1), (CR^(a)R^(a1))_(n)OC(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)NR^(a)C(O)OR^(a1),(CR^(a)R^(a1))_(n)NR^(a)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1),(CR^(a)R^(a1))_(n)NR^(a)SO₂R^(a3),(CR^(a)R^(a1))_(n)NR^(a)SO₂NR^(a)R^(a1), —(CR^(a)R^(a1))_(n)—C₃₋₁₀carbocycle substituted with 0-2 R^(c1), and —(CR^(a)R^(a1))_(n)-5-14membered heterocycle consisting of carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R^(c1); R^(c1), at each occurrence, is independently selectedfrom: H, C₁₋₄ alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)R^(a),C(O)OR^(a), C(O)NR^(a)R^(a), and S(O)_(p)R^(a); R⁵, at each occurrence,is selected from: C₁₋₁₀ alkyl substituted with 0-2 R^(b), and C₁₋₈ alkylsubstituted with 0-2 R^(e); R^(e), at each occurrence, is selected from:phenyl substituted with 0-2 R^(b) and biphenyl substituted with 0-2R^(b); R⁶, at each occurrence, is selected from: phenyl, naphthyl, C₁₋₁₀alkyl-phenyl-C₁₋₆ alkyl-, C₃₋₁₁ cycloalkyl, C₁₋₆ alkylcarbonyloxy-C₁₋₃alkyl-, C₁₋₆ alkoxycarbonyloxy-C₁₋₃ alkyl-, C₂₋₁₀ alkoxycarbonyl, C₃₋₆cycloalkylcarbonyloxy-C₁₋₃ alkyl-, C₃₋₆ cycloalkoxycarbonyloxy-C₁₋₃alkyl-, C₃₋₆ cycloalkoxycarbonyl, phenoxycarbonyl,phenyloxycarbonyloxy-C₁₋₃ alkyl-, phenylcarbonyloxy-C₁₋₃ alkyl-, C₁₋₆alkoxy-C₁₋₆ alkylcarbonyloxy-C₁₋₃ alkyl-, [5-(C₁-C₅alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl,[5-(R^(a))-1,3-dioxa-cyclopenten-2-one-yl]methyl,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, —C₁₋₁₀ alkyl-NR⁷R^(7a),—CH(R⁸)OC(═O)R⁹, and —CH(R⁸)OC(═O)OR⁹; R⁷ is selected from: H, C₁₋₁₀alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆alkyl-; R^(7a) is selected from H, C₁₋₁₀ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-; R⁸ is selected from Hand C₁₋₄ linear alkyl; R⁹ is selected from H, C₁₋₈ alkyl substitutedwith 1-2 R^(f), C₃₋₈ cycloalkyl substituted with 1-2 R^(f), and phenylsubstituted with 0-2 R^(b); R^(f), at each occurrence, is selected from:C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₅ alkoxy, and phenyl substituted with0-2 R^(b); n, at each occurrence, is selected from: 0, 1, 2, 3, and 4;p, at each occurrence, is selected from: 0, 1, and 2; and r, at eachoccurrence, is selected from: 0, 1, 2, 3, and 4; provided that: (i) whenrings B and C form tetrahydroisoquinoline and A is —C(O)NHOH, then R¹ isother than {4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl,{(2-hydroxybenzoyl)amino)}benzenesulfonyl,{(4-fluorophenyl)methoxy}benzenesulfonyl, or{(4-methoxyphenyl)carbamate}benzenesulfonyl; (ii) when rings B and Cform tetrahydro-furo[2,3-c]pyridine, A is —C(O)NHOH, and U is SO₂, thenZ is other than phenyl; (iii) when rings B and C formtetrahydro-1H-[1,4]benzodiazepine, A is —C(O)NHOH, U is SO₂, then Z isother than phenyl; (iv) when U is SO₂, then U^(a)-X^(a)-Y^(a) is otherthan —OCH₂—C≡C—, —NHCH₂—C≡C—, —CH₂CH₂—C≡C— or —SCH₂—C≡C—; (v) when U isSO₂ and Z is phenyl, then U^(a) is other than OC(O).
 2. A compoundaccording to claim 1, wherein; A is selected from: —C(O)NHOH,—C(O)NHOR⁵, —C(O)NHOR⁶, —N(OH)COR⁵, and —N(OH)CHO; ring B including B¹and B² is a 5-6 membered heterocyclic ring substituted with 0-1 R²; ringC is a 6 membered aryl or 5-6 membered heteroaryl consisting of 1-6carbon atoms and 0-4 heteroatoms selected from O, N, and S(O)_(p); ringC is substituted with 0-1 R³ and 0-1 R⁴; X is absent or is selectedfrom: C₁₋₄ alkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene; Y is absent;Z is selected from: a C₃₋₁₁ carbocycle substituted with 0-5 R^(b); and a5-11 membered heterocycle consisting of carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-5 R^(b); U^(a) is absent or is selected from: O, NR^(a1), C(O),C(O)O, C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), and S(O)_(p)NR^(a1); X^(a) isabsent or is selected from: C₁₋₄ alkylene, C₂ alkenylene, and C₂alkynylene; Y^(a) is absent or is selected from: O and NR^(a1); providedthat U^(a)-X^(a)-Y^(a) forms a spacer of two or more atoms, other than—CH═CH— or —C≡C—; Z^(a) is selected from: a C₃₋₁₃ carbocycle substitutedwith 0-5 R^(c); and a 5-10 membered heterocycle consisting of carbonatoms and 1-4 heteroatoms selected from the group consisting of N, O,and S(O)_(p) and substituted with 0-5 R^(c); provided that U, Z, U^(a),Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O,S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R³ is selected from:H, C₁₋₆ alkyl substituted with 0-1 R^(b), C₂₋₆ alkenyl substituted with0-1 R^(b), C₂₋₆ alkynyl substituted with 0-1 R^(b), C₃₋₆ carbocyclesubstituted with 0-2 R^(b), —CH₂—C₃₋₆ carbocycle substituted with 0-2R^(b), a 5-6 membered heterocycle consisting of carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-2 R^(b), and —CH₂-5-6 membered heterocycle consistingof carbon atoms and 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) and substituted with 0-2 R^(b); R^(a), at eachoccurrence, is independently selected from: H and C₁₋₄ alkyl; R^(a1), ateach occurrence, is independently selected from: H, C₁₋₄ alkyl, phenyland benzyl; alternatively, R^(a) and R^(a1) when attached to a nitrogenare taken together with the nitrogen to which they are attached form a 5or 6 membered heterocycle consisting of carbon atoms and from 0-1additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p); R^(b),at each occurrence, is independently selected from: C₁₋₆ alkyl, OR^(a),Cl, F, Br, ═O, —CN, NR^(a)R^(a1), C(—O)R^(a), C(O)OR^(a),C(O)NR^(a)R^(a1), NR^(a)C(O)R^(a), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3),CF₃, and OCF₃; R^(c), at each occurrence, is independently selectedfrom: C₁₋₆ alkyl substituted with 0-1 R^(c1), C₂₋₆ alkenyl substitutedwith 0-1 R^(c1), C₂₋₆ alkynyl substituted with 0-1 R^(c1), OR^(a), Cl,F, Br, ═O, —CN, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a1), (CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1),C₃₋₆ carbocycle and a 5-6 membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p); R⁵, at each occurrence, is selected from: C₁₋₆ alkylsubstituted with 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);R⁷ is selected from: H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl-C₁₋₃alkyl-, and phenyl-C₁₋₆ alkyl-; R^(7a) is selected from: H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₆ cycloalkyl-C₁₋₃ alkyl-, and phenyl-C₁₋₆ alkyl-; andR⁹ is selected from: H, C₁₋₆ alkyl substituted with 1-2 R^(f), C₃₋₆cycloalkyl substituted with 1-2 R^(f), and phenyl substituted with 0-2R^(b); provided that: (i) when rings B and C form tetrahydroisoquinolineand A is —C(O)NHOH, then R¹ is other than{4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl,{(2-hydroxybenzoyl)amino)}benzenesulfonyl,{(4-fluorophenyl)methoxy}benzenesulfonyl, or{(4-methoxyphenyl)carbamate}benzenesulfonyl; (ii) when rings B and Cform tetrahydro-furo[2,3-c]pyridine, A is —C(O)NHOH, and U is SO₂, thenZ is other than phenyl.
 3. A compound according to claim 2, wherein; Ais selected from: —C(O)NHOH, and —N(OH)CHO; U-X is SO₂, C(O), orC(O)CH₂; Z is phenyl substituted with 0-3 Rb or pyridyl substituted with0-3 R^(b); U^(a) is absent or is selected from: O, NR^(a1), C(O),C(O)NR^(a1), S(O)_(p), and S(O)_(p)NR^(a1); X^(a) is absent or isselected from: C₁₋₄ alkylene, C₂ alkenylene, and C₂ alkynylene; providedthat U^(a)-X^(a)-Y^(a) forms a spacer of two or more atoms and is otherthan —CH═CH— or —C≡C—; Z^(a) is a C₅₋₆ carbocycle substituted with 0-3R^(c) or a 5-10 membered heteroaryl containing from 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-3 R^(c); provided that Z, U^(a), Y^(a), and Z^(a) do not combineto form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) orS(O)_(p)—S(O)_(p) group; R^(a), at each occurrence, is independentlyselected from: H and C₁₋₄ alkyl; R^(a1), at each occurrence, isindependently selected from: H, C₁₋₄ alkyl, phenyl and benzyl; R^(b), ateach occurrence, is independently selected from: C₁₋₄ alkyl, OR^(a), Cl,F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃; R^(c), at each occurrence,is independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a), (CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1), andphenyl; and R⁵, at each occurrence, is selected from: C₁₋₄ alkylsubstituted with 0-2 R^(b), and C₁₋₄ alkyl substituted with 0-2 R^(e);provided that: (i) when rings B and C form tetrahydroisoquinoline and Ais —C(O)NHOH, then R¹ is other than{4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl,{(2-hydroxybenzoyl)amino)}benzenesulfonyl or{(4-fluorophenyl)methoxy}benzenesulfonyl; (ii) when rings B and C formtetrahydro-furo[2,3-c]pyridine, A is —C(O)NHOH, and U is SO₂, then Z isother than phenyl.
 4. A compound according to claim 3, wherein; A is—C(O)NHOH; Z is phenyl substituted with 0-1 R^(b) or pyridyl substitutedwith 0-1 R^(b); U^(a) is absent or is O; X^(a) is absent or is CH₂ orCH₂CH₂; Y^(a) is absent or is O; provided that U^(a)-X^(a)-Y^(a) forms aspacer of two or more atoms, other than —CH═CH— or —C≡C—; Z^(a) isselected from: phenyl substituted with 0-3 R^(c), pyridyl substitutedwith 0-3 R^(c), and quinolinyl substituted with 0-3 R^(c); provided thatZ, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, orO—O group; R^(a), at each occurrence, is independently selected from: H,CH₃, and CH₂CH₃; R^(a1), at each occurrence, is independently selectedfrom: H, CH₃, and CH₂CH₃; R^(a2), at each occurrence, is independentlyselected from: H, CH₃, and CH₂CH₃; R^(c), at each occurrence, isindependently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(n)C(O)R^(a1),(CR^(a)R^(a1))_(n)C(O)OR^(a), (CR^(a)R^(a1))_(n)C(O)NR^(a)R^(a1),(CR^(a)R^(a1))_(n)S(O)_(p)R^(a3), and (CR^(a)R^(a1))_(n)SO₂NR^(a)R^(a1);r, at each occurrence, is selected from 0, 1, 2, and 3; and, n, at eachoccurrence, is selected from 0, 1, 2, and 3; provided that: (i) whenrings B and C form tetrahydroisoquinoline and A is —C(O)NHOH, then R¹ isother than {4-((2-methyl-4-quinolinyl)methoxy)phenyl}acetyl or{(4-fluorophenyl)methoxy}benzenesulfonyl; (ii) when rings B and C formtetrahydro-furo[2,3-c]pyridine, A is —C(O)NHOH, and U is SO₂, then Z isother than phenyl.
 5. A compound according to claim 1, wherein thecompound is selected from the group:N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxamide;N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxamide;N-hydroxy-7-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-6-carboxamide;N-hydroxy-7-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-6-carboxamide;N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-5,6,7,8-tetrahydropyrido[3,4-b]-pyrazine-7-carboxamide;N-hydroxy-6-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-7-carboxamide;N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine-6-carboxamide;N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine-6-carboxamide;N-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}acetyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine-6-carboxamide;andN-hydroxy-5-({4-[(2-methyl-4-quinolinyl)methoxy]phenyl}sulfonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine-6-carboxamide;or a pharmaceutically acceptable salt form thereof.
 6. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt form thereof.
 7. A method for treatingan inflammatory disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt form thereof.
 8. A methodcomprising: administering a compound according to claim 1 or apharmaceutically acceptable salt form thereof, in an amount effective totreat a condition or disease mediated by MMPs, TACE, or a combinationthereof.
 9. A method of treating a condition or disease mediated byMMPs, TACE, aggrecanase, or a combination thereof in a mammal,comprising: administering to the mammal in need of such treatment atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt form thereof.
 10. A method of treatingaccording to claim 9, wherein the disease or condition is selected fromacute infection, acute phase response, age related macular degeneration,alcoholic liver disease, allergy, allergic asthma, anorexia, aneurism,aortic aneurism, asthma, atherosclerosis, atopic dermatitis, autoimmunedisease, autoimmune hepatitis, Bechet's disease, cachexia, calciumpyrophosphate dihydrate deposition disease, cardiovascular effects,chronic fatigue syndrome, chronic obstruction pulmonary disease,coagulation, congestive heart failure, corneal ulceration, Crohn'sdisease, enteropathic arthropathy, Felty's syndrome, fever, fibromyalgiasyndrome, fibrotic disease, gingivitis, glucocorticoid withdrawalsyndrome, gout, graft versus host disease, hemorrhage, HIV infection,hyperoxic alveolar injury, infectious arthritis, inflammation,intermittent hydrarthrosis, Lyme disease, meningitis, multiplesclerosis, myasthenia gravis, mycobacterial infection, neovascularglaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis,polymyositis/dermatomyositis, post-ischaemic reperfusion injury,post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonaryemphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter'ssyndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis,scleroderma, sepsis syndrome, Still's disease, shock, Sjogren'ssyndrome, skin inflammatory diseases, solid tumor growth and tumorinvasion by secondary metastases, spondylitis, stroke, systemic lupuserythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'sgranulomatosis.
 11. A method for treating inflammatory disorders,comprising: administering, to a host in need of such treatment, atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof, in combination with oneor more additional anti-inflammatory agents selected from selectiveCOX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthaseinhibitors, p38 MAP kinase inhibitors, TNF-α inhibitors, TNF-βsequestration agents, and methotrexate.